FR2758819A1 - INDOMETACIN CALCIUM AND ITS PREPARATION - Google Patents

Abstract

Pentahydrate indometacine calcium salt of formula (I) is new, and contains ≤ 0.5 wt. % free indometacine and/or ≤ 0.2 wt. % degraded indometacine.

Description

The subject of the present invention is: a new salt of indomethacin,

  pharmaceutical compositions containing, as active ingredient, said new salt of indomethacin; a process for preparing said new salt and in particular a variant

optimized of it.

  Indomethacin or 1- (p-chlorobenzoyl) -5-methoxy-2- acid

  methylindole-3-acetic acid, corresponding to the following formula: TO-C1

"N CH3

CH303

CH3 O CH2COOH

  is a well known compound, since the early 1960s, which has interesting pharmacological properties. A process for synthesizing said compound has in particular been described in US-A-3,161,654. The compound has been proposed for many years as an anti-inflammatory. It is an inhibitor of prostaglandins. However, it has a major disadvantage: its gastro-toxicity. Applicant has shown that the calcium salt of said compound, present, relative to the acid form, while maintaining an equivalent pharmacological activity: - orally, decreased toxicity;

  - rectally, better local tolerance.

  Such results are quite surprising insofar as the in vivo hydrolysis of said calcium salt (as is the case with magnesium and lithium salts, for example) and so at the event

  toxicity of indomethacin acid.

  Said calcium salt of indomethacin or indomethacin calcium constitutes

  the first object of the present invention.

  The remarkable improvement in the efficiency / tolerance couple of this salt led the Applicant to develop a particularly efficient manufacturing process, which constitutes another object of the present invention. According to its first object, the present invention thus relates to indomethacin calcium. In the context of this first object, it concerns, more particularly, said indomethacin calcium hydrated form and responding, in particular: - to the empirical formula, hereinafter: C38H30Cl2,2NO8Ca, 5H2O; - the structural formula, hereinafter:

N 1CH2

C3 Ca2 +, 5H20

H3CO CH2COO

  The relative mass of this new compound is Mr = 843.68.

  Indomethacin calcium is in the form of a yellow crystalline powder, odorless or substantially odorless, practically insoluble in water, in chloroform, in ether and in acetonitrile, easily soluble in water.

  dimethylformamide, soluble in tetrahydrofuran.

  The melting point, with decomposition, of calcium indomethacin is

  close to 240 C (that of indomethacin (acid) is: 158 to 162-C).

  In the context of its first subject, the present invention relates more particularly to said indomethacin calcium, containing a content of less than or equal to 0.5% by weight of free indomethacin (acid) and / or a content of less than or equal to 0.2 % by weight of degradation product (s) of indomethacin. These are preferred forms of the product of the invention. Particularly preferred forms are those which contain both: a free indomethacin content of less than or equal to 0.5% by weight; and a degradation product content (s) of the lower indomethacin or

equal to 0.2% by weight.

  Said preferred and particularly preferred forms can be obtained directly after optimized variants of implementation of the process of the invention or at the end of a complementary purification step.

  following a non-optimized implementation of the method of the invention.

  It is pointed out here, for all intents and purposes, that the main degradation products of indomethacin consist of parachlorobenzoic acid and 5-methoxy-2-methyl-3-indole acetic acid. This is well known to man

of career.

  As indicated above, indomethacin calcium according to the invention retains all the pharmacological properties of indomethacin (free). It can therefore be used in the same therapeutic indications. In addition, it offers the advantage of having a lower toxicity and a better tolerance than

said indomethacin (free).

  Indeed, the respective comparisons of DE50 (50% effective dose) and LD50 (50% lethal dose), in the rat, of said calcium indomethacin and of said

  free indomethacin are clearly to the advantage of said calcium indomethacin.

  The results obtained are given in the following table: Indomethacin Calcium Indomethacin (mg / kg) (mg / kg) Prior art Invention

DE50 3 2.5

LD50 28 45

  Therapeutic index: DE50 9.3 18 DL25 According to its second subject, the present invention therefore logically relates to pharmaceutical compositions or medicaments which contain a pharmacologically (therapeutically) active amount of indomethacin calcium. Said indomethacin calcium - active principle - is advantageously incorporated into a pharmaceutically acceptable excipient, carrier or vehicle. Said pharmaceutical compositions of the invention may in particular be formulated as galenic preparations suitable for administration orally, rectally, by injection or for local, dermal or ophthalmic applications. It is clear that the indomethacin calcium of the invention is advantageously substituted for the indomethacin acid (free) of the prior art, in all the therapeutic indications of the latter; familiar therapeutic indications

to the skilled person.

  According to its third object, the present invention relates to a method for

  the preparation of said calcium indomethacin.

  Said method consists of the salification of indomethacin (free acid) with calcium carbonate; said salification, carried out according to the reaction + H20

  2 Indomethacin + Ca C03 ((Indom.) 2 Ca + CO-

anhydrous

  can be a quantitative reaction.

  The stoichiometric molar proportions of the reagents (indomethacin

CaCO3) are 2: 1.

  During its formation, indomethacin calcium is in the form of a yellow powder, which is collected and then generally dried, in a ventilated oven, in particular under the following conditions: at 60 C, for 12 hours. The dry pale yellow powder obtained is then generally left in the ambient air until

that its mass remains constant.

  The salification reaction is carried out in a solvent medium,

advantageously in aquicultural milicu.

  At the end of the salification reaction, as indicated above, the indomethacin calcium powder obtained is recovered after drying. Said powder is, if necessary, purified by washing with suitable organic solvents (such as chloroform) in order to reduce or even eliminate, as far as possible, free indomethacin and the degradation product (s). of the indomethacin it contains. Advantageously, in the context of the present invention, the preferred and particularly preferred forms of indomethacin calcium are obtained; namely forms, which contain: a content of free indomethacin, less than or equal to 0.5% by weight, and / or (advantageously and) a content of degradation product (s), less than or equal to 0, 2% by weight. To achieve this goal, it may be necessary, as indicated above, to follow the salification step (carried out under non-optimized conditions) of a purification step but, according to an advantageous variant of the process of the invention, one can directly obtain the product meeting the purity criteria above. To this end, it is necessary to implement the

  salification under adequate controlled conditions.

  The implementation of the process of the invention, under such conditions, explained below, is a particularly preferred variant of the claimed process. According to said preferred variant, the reagents indomethacin (free) and calcium carbonate (CaCO3) are reacted: in an aqueous medium: the intervention of water, as a solvent, is widely preferred, for reasons (especially economical , ecological, reaction neutrality, non-toxicity and purity of the expected product) that the skilled person easily understands; in a molar proportion of between 2: 1 and 2: 4, advantageously in the stoichiometric proportion 2: 1: the calcium carbonate is used at least in stoichiometric quantity or even in amounts greater than this, so as to maximum salt free acid (indomethacin free) and thus minimize the presence of said acid in the final product. If the amount of intervention of said calcium carbonate is limited to said stoichiometric amount, the handling of the excess calcium carbonate is dispensed with. The risk of formation of degradation products of indomethacin is also minimized, insofar as said formation is favored in an alkaline medium. If said calcium carbonate is involved in an amount greater than said stochiometric amount, indomethacin calcium is obtained with the excess of said calcium carbonate (relative to the stoichiometric proportion). This excess is positive insofar as it allows a better management of the process (made less sensitive to variations of the key parameters of the reaction) and negative for the reason indicated above. A reasonable compromise is needed. At the end of the reaction, the excess of CaCO 3 is not unduly troublesome since said calcium carbonate may in particular be suitable as a pharmaceutically acceptable excipient for the formulation of prepared calcium indomethacin; at a temperature of less than or equal to 30 ° C., it is recommended to use salification with CaCO3 at a temperature of between 15 and 30 ° C., advantageously at a temperature of between 20 and 25 ° C. The temperature of implementation of the reaction corresponds to a compromise between the speed of said

  reaction and the risk of formation of indomethacin degradation product (s).

  It is strongly recommended to maintain the reactor below 30 C, to ensure, in the final reaction mixture, a tencur product (s) degradation less than 0.2% by weight; under conditions where the accumulation, in the reaction medium. CO-formed is minimized or even canceled: the salification is indeed quantitative under the condition of sufficiently stirring the reaction mixture and avoiding, in it, the accumulation of carbon dioxide. In such a reaction, the stirring of the reaction mixture ensures, on the one hand, in a conventional manner, the homogeneity of the distribution of the reactive products and, on the other hand, to promote the elimination of the CO2 generated. by the reaction. The method of the invention is therefore, in the context of

  this advantageous variant, put cn work with effective stirring.

  Apart from the agitation, for the degassing of the CO2 formed, the two following techniques can advantageously be implemented, independently or even conjointly: - submission of the editor to an intermittent or continuous vacuum (generally, in the minutes which Following the addition of CaCO 3, the production of CO 2 is important and tends to foam the reaction mixture, so it was considered appropriate to apply a vacuum, controlled, intermittently, depending on the foaming level, at the beginning of the process. This vacuum usually occurs between 0.1 and 0.5 bar, and after this initial phase of ammonification (which can be repeated if CaCO3 is added fractionally (see below), the applied vacuum is usually maintained between 0.2 and 1 bar, preferably between 0.5 and 0.7 bar Depending on the type of reactor (mixer) used, a higher vacuum can be applied) - the introduction into said reactor of reagent CaCO3 , in a fractional way (from thus to limit the concentration of CO2 in the reaction mixture). To obtain the first effect expected by stirring - namely a sufficient homogenization - care is taken to intervene depending on the type of reactor (mixer) and the quantities used, the appropriate amounts of solvent (water, advantageously). Said solvent (water, advantageously) is advantageously involved in the amounts below: the proportion of solvent, expressed in liters, of the reaction mixture is between 2 and 10 times, preferably between

  2 and 7 times, the weight of free indomethacin (reagent), expressed in kilograms.

  At the end of the implementation, more or less optimized, of the process of the invention, it is recalled that a paste is obtained which should generally be dried (especially in an oven) and then left to ambient air, until its

mass remains constant.

  As the reader will have understood, said paste may optionally contain, in addition to the expected product (indometacin calcium), calcium carbonate (excess reagent), free indomethacin (advantageously less than 0.5% by weight ), degradation products of indomethacin (advantageously

less than 0.2% by weight).

  The method of the invention described above is particularly interesting in that: it can be implemented at different scales of quantities (laboratory, pilot, industrial production); its extrapolation raises no particular difficulty; it can be used in different types of reactors (mixers); - it offers advantages, which would not be obtained together, nor with other calcium derivatives (such as, for example, calcium hydroxide or calcium

  calcium glycerophosphate) or with other alkaline or alkaline

  earthy: namely: + an absence of residual third products, insofar as carbon dioxide (CO2) can be easily eliminated; + an implementation of a reduced number of reagents: indomethacin (free), calcium carbonate (CaCO3), the solvent (water, advantageously); + production conditions and cost prices, compatible with an industrial operation; + obtaining (advantageously direct) a product whose quality, stability, activity and tolerance are compatible with a pharmaceutical use. Those skilled in the art, on reading the foregoing, have already grasped the whole point of the present invention, which proposes both: an original form of an active principle of the prior art; original form which has retained the therapeutic properties of said active ingredient of the prior art and no longer has its toxicity; a method, simple and efficient, for the preparation of said form

  the laboratory, the pilot and the industrial scale.

  According to its last object, the present invention relates to calcium indomethacin which can be obtained by the advantageously optimized variants of the process of the invention and therefore containing a content of less than or equal to 0.5% by weight of free indomethacin and / or or a content not exceeding 0.2% by weight

  of product (s) of degradation of indonothacin.

  The present invention is hereby illustrated, in no way limiting, by the following examples. It is more precisely illustrated by the

  results given in Table 1 below.

  La Demandercsse has implemented, under different conditions, the process of the invention, to obtain, at different yields and degrees of purity,

Indomethacin calcium.

  This method of the invention has been implemented according to various variants, both at the laboratory scale (reactor 1) and the pilot scale (reactor 100 1). Whatever the variant embodiment, the reactants (indometacinc librc + CaCO3), in aqueous medium, were introduced from the start into different

  proportions, in the reactor used.

  Said used reactor, of 1 I (laboratory scale) or 100 1 (pilot scale) consists of a mixer either of the vane mixer type, or of the mixer type for pasty product (more specifically, MOLTOMAT reactor equipped

its agitation system).

  a) The synthesis of indomethacin calcium was carried out in vane mixers: - 100 l, for batch A production; - of 1 1, for the production of lots B and C; under the following conditions: - at a temperature between 25 and 30C; - at atmospheric pressure; in an aqueous medium, in the following proportions: volume of water (in liters) / weight of indomethacin (in kg) = 10;

  with different molar ratios of the reagents: indomethacin: CaCO3.

  The results obtained with regard to the purity of indomethacin produced

  in the first part of Table 1 below.

  b) The synthesis of indometacin calcium was carried out in mixers for pasty product (MOLTOMAT reactors): - 100 I, for the production of lots D, E, F, I, J, K; - by 1 1, for the production of lots G and H; under the following conditions: - under a vacuum of 0.1 - 0.5 bar; at a temperature between 25 ° and 30 ° C., for batches I, J, K and without control of said temperature for batches D, E, F, G, H, which temperature is raised to 50-60 C for said batches D, E and F); under various stirring conditions: low agitation (lots D and E) strong stirring (lots F, G, H, J, K) - Cen aqueous media; in the following proportions: + volume of water (in liters) / weight of indometacin (in kg) = 10 + or volume of water (cn liters) / weight of indomethacin (in kg) between 3 and 7;

  with different molar ratios of the reagents: indomethacin: CaCO3.

  The results obtained, as to the purity of the indomethacin produced,

  appear in the second part of Table 1 below.

Table 1

  Proportions Free Indomethacin Degradation Products *** Indomethacin: CaCO3 (wt% dry) (ac MMIA + ac.p.CB) (wt% dry) In vane blender 2: 3.57 (lot A) 0.12 0.10

2: 1 (stoichiometric) (lot B) 0.12 -

  2: 0.5 (batch C) 45.7 t (which corresponds to -50% indomethacin combined in the form of indomethacin calcium) In a mixer for pasty product without cooling 2: 1 * (stoichiometric) (batch D ) 7 2: 1 * (stoichiometric) (lot E) 3 2: 1 ** (stoichiometric) (lot F) 0, 15 0.27 2: 1.1 * (lot G) 0.12 0.06 2: 1.5 * (lot H) 0.16 0.03 - with cooling * 2: 1 (stoichiometric) (lot 1) 0.19 0.13 2: 1 (stoichiometric) (lot J) 0, 0.07 2: 1 (stoichiometric) (batch K) 0.11 0.11 * Volume of water (in liters) / weight of indomethacin (in kg) = 10 * * Volume of water (in liters ) / weight of indomethacin (in kg):> 3 and <7 ** Ac.MMIA = 5-methoxy-2-methyl-3-indole acetic acid; Ac.p-CB = parachlorobenzoic acid The consideration of said results calls for the following comments: the salification, according to the invention, of indomethacin is quantitative; the weight of free indomethacin in the product obtained (indometacin calcium) is <0.5% for the stoichiometric proportions (lots B, F, I, J, K). Excess CaCO3 of 357% (lot A), 50% (lot H) and 10% (lot G) also make it possible to obtain indometacin calcium with a weight ratio of free indomethacin <0.5%. With the proportions of indomethacin: CaCO3 of 2: 0.5, the weight ratio of free indomethacin in the product is around 50%; when agitation is not sufficient (lots D and E), i.e. when CO 2 is not sufficiently removed, the level of free indomethacin increases; (this rate could be decreased by increasing the proportion of CaCO3); when the temperature of the reaction medium exceeds 30 ° C., the appearance of the degradation products is favored; their weight ratio becomes greater than 0.2% (lot F). Cooling the reactor, so as to maintain said temperature of the reaction medium less than or equal to 30 ° C, provides a very pure product; the results, obtained for batches G and H, in the absence of cooling, are good, insofar as the quantities of reagents put in

have remained weak.

  The process of the invention, according to its optimized variants, makes it possible to obtain indometacin calcium directly on an industrial scale: with a free indometacin content of less than or equal to 0.5% by weight; with a rate of degradation product (s) of less than or equal to 0.2% by weight.

Claims (12)

claims 1. Indomethacin calcium.   2. Calcium indomethacin in hydrated form, in particular having the following structural formula: N 93 CH 3 Ca 2+, 5H 2 O 2 O H3CO CH2COO   3. Indometacin calcium according to one of claims 1 or 2,   characterized in that it contains a tencur less than or equal to 0.5% by weight of free indometacine and / or a tencur less than or equal to 0.2% by weight of   degradation product (s) of indomethacin.   4. Pharmaceutical compositions characterized in that they contain a pharmacologically active amount of indomethacin calcium   according to any one of claims 1 to 3, advantageously incorporated in   a carrier, carrier or vehicle technically acceptable.   5. Pharmaceutical compositions according to claim 4, characterized in that they consist of acceptable galenic preparations for oral administration, by voicecal, injectable voic or for   local, clinical or ophthalmic applications.   6. Process for the preparation of indiumetacin calcium characterized in that it comprises the reaction, in a solvent medium, advantageously in a medium   water, indomethacin (acid) with calcium carbonate.   7. Process according to claim 6, characterized in that it comprises the recovery, after drying, of the indomethacin calcium powder obtained and if necessary the purification of said powder, by washing with suitable organic solvents, to reduce the contents. free indomethacin and the product (s) of degradation of ladle powder.   8. Method according to one of claims 6 or 7, characterized in that said reaction is carried out: - an aqueous medium; with the indomethacin (free) reagents: calcium carbonate in a molar proportion of between 2: 1 and 2: 4, advantageously in a molar proportion of 2: 1; at a temperature below 30 ° C; under conditions where the accumulation, in the reaction medium,   CO2 formed is minimized or even canceled.   9. Method according to any one of claims 6 to 8, characterized   in that it is implemented with agitation; with, advantageously, application of an intermittent or continuous vacuum and / or introduction of calcium carbonate into   the reaction mixture fractionally.   10. Method according to any one of claims 6 to 9, characterized   in that the proportion of solvent, advantageously the proportion of water, expressed in liters, of the reaction mixture is between 2 and 10 times, advantageously   between 2 and 7 times, the weight of indomethacin (free), expressed in kilograms.   11. Method according to any one of claims 6 to 10,   characterized in that the paste obtained at the end of the reaction is dried and then left   ambient air until its mass remains constant.   12. Indometacin calcium obtainable directly by the process according to any one of Claims 8 to 11, characterized in that it contains a tencur less than or equal to 0.5% by weight of indometacin free ct / or a tencur less than or equal to 0.2% by weight of degradation product (s) dc indomethacin.